The most important genetic risk factor for Alzheimer's disease (AD) is the APOE gene. APOE encodes the apolipoprotein E (apoE) protein, the main apolipoprotein in the central nervous system (CNS). ApoE interacts with the family of low density lipoprotein receptors, and these apoE receptors are expressed by neurons and glia. Thus, apoE receptors regulate apoE metabolism and mediate the effects of apoE on neuronal signaling, APP processing, neurotoxicity, and synaptic function. The goal of this Program is to take advantage of the overlapping interests and diverse expertise of five scientists examining the biology of apoE and apoE receptors in the CNS. The Aims of this Program are to define the expression and function of apoE receptors in the CNS, and how their functions are regulated by the three apoE isoforms and cellular proteolytic events. These projects also include an examination of the generation and function of soluble receptors. In Project 1, Dr. LaDu will examine how apoE receptors and beta-amyloid peptide mediate the metabolism of the 3 human apoE isoforms. In Project 2, Dr. Estus will test whether genetic variations within apoE receptor genes alter their functions and define whether these variations affect the risk of AD. In Project 3, Dr. Bu will define factors that affect the trafficking and processing of one of these receptors, LRP, and determine how LRP affects the amyloid precursor protein. In Project 4, Dr. Rebeck will examine another brain apoE receptor, ApoER2, and determine how its processing is regulated, and define the fate of soluble apoE receptors. In Project 5, Dr. Weeber will determine the mechanisms of apoE-dependent modulation of synaptic plasticity and in vivo effects of apoE receptor activation on neurobehavior and neuroplasticity. THE CORES INCLUDE: A) Administrative Core (for fiscal management, maintaining good communications between the five sites and overseeing a yearly symposium on apoE and apoE receptors); B) Molecular Cell Biology Core (for conducting standardized assays of apoE, apoE receptors, and Abeta, for developing, characterizing and distributing new common reagents, and for generating new transgenic mouse models as part of this Program); and C) Transgenic Core (all mice are maintained at Taconic, for distributing transgenic mouse models of AD and mice with altered levels of apoE receptors). This Program will thus provide new and valuable information about how apoE and apoE receptors affect the pathogenesis of Alzheimer's disease.